There are growing evidence that a variety of chronic diseases are triggered, sustained or reinforced by systemic translocation of intestinal lipopolysaccharides (LPS) [Pinzone et al. 2012]. Bacterial lipopolysaccharide (LPS) is thought to be responsible for the multiple organ dysfunction syndrome [Louis et al. 2013] and the acute respiratory distress syndrome [Bernard et al., Am J Respir Crit Care Med 1994; 149: 818-824]. Both in vitro and in vivo studies have shown that administration of LPS causes a variety of reactions [Windsor et al. 1993; Louis et al. 2013]. In vitro studies indicate that LPS does not directly induce apoptosis of endothelial cells. Several investigations have pointed to LPS-induced tumor necrosis factor alpha (TNF-α) as the cause of endothelial cell apoptosis [Bazzoni and Beutler N Engl J Med 1996; 334: 1717-1725; Buchman et al. Am J Physiol 1993, 265: H165-170; Polunovsky et al. Exp Cell Res 1994, 214: 584-594; Robaye et al. Am J Pathol 1991, 138: 447-453; Takei et al., J Gastroenterol Hepatol, 1995, 10: 65-67; Munshi et al. J Immunol. 2002 Jun. 1; 168(11):5860-6].
LPS is also known to be attracted by CD14 on the surface of monocytic cells [Devitt et al. 1998; Tapping et al. Nature 1998; 392: 505-509]. Interestingly, it is widely believed that this reflects the first step in signal transduction via LPS.
Another question from the clinical perspective concerns the impact of a therapeutic intervention involving the LPS turnover on the overall apoptotic response. In this context, in the long-term, immunoglobulins may exert several beneficial immunological effects in patients affected with subclinical immune activation. This is primarily reflected by antibodies against bacterial LPS molecules and Lactoferrin which also exerts strong inhibitory LPS activity [Bellamy et al. Biochim Biophys Acta 1992; 1121: 130-136, Appelmelk et al Infection and Immunity 1994; 62(2): 2628-2632; Inubushi et al. 2012]. However, the whole spectrum of effects and specificities of the effector mechanisms of oral anti-LPS immunoglobulins has not been fully investigated. One key effector mechanism may be related to apoptosis in monocytic cells. The inventors have shown that a new therapeutic approach based on an oral administration of anti-LPS antibodies (immunoglobulins) lead to a significant or complete symptom relief in more than 50% of the patients in need of such treatment, e.g. with chronic pain syndromes (unpublished data).
The fit-for-purpose, scientific validation, and the overall clinical qualification of parameters for diseases triggered by LPS translocation and inflammation could dramatically change the current outlook on treatment of such diseases.
A predictive biomarker is associated with the likelihood of sensitivity or resistance (response) to a specific therapy (drug). The concept of a predictive biomarker is usually applied to individual patients with the goal of tailoring therapy to maximize efficacy. In more specific and practical terms, a predictive biomarker as herein demonstrated could assist the clinician in deciding which patients are responders to the anti-LPS immunoglobulin treatment.
Accordingly, one object of the present invention is to provide a reliable prognosis assay for determining individual patient clinical benefit of oral immunoglobulin therapy (i.e responder to oral anti-LPS immunoglobulin treatment) and for avoiding administering the anti-LPS immunoglobulin treatments to non-responders. Methods for selecting the responders prior to treating patients would allow for an individualized therapeutic decision, which in turn is of great psychological benefit for the patients, improves health outcomes and provides economic benefit for the community.
Another object of the present invention is to provide a prognosis assay which could be performed from a biological sample of the patient, preferably a blood sample.
A further object of the present invention is to provide a prognosis assay that would be highly specific, i.e. whereas at least 80%, or 90% or more preferably at least 95% and even more preferably at least 98% of the patients that are diagnosed as responder according the assay are indeed true responders to the LPS immunoglobulin treatments.
In order to fulfil this need, the inventors performed a laboratory screen focusing on a broad spectrum of immune parameters in patients before and after oral anti-LPS immunoglobulin treatment and comparing the results to those of healthy control individuals.
Thus, according to the method of the present invention, a selection of the patients can take place before these individuals receive the anti-LPS immunoglobulin treatment. This would relief mental stress to the patients and save costs. The results of the screen performed by the inventors demonstrated that 15 specific parameter profiles (i.e. the predictive biomarkers) enable to differentiate between responders and non-responders to a planned anti-LPS immunoglobulin treatment.